Cocaine remains a major public health concerns due to a continuing increase in the number of emergency room admissions following cocaine use. Cardiovascular complications represent a large proportion of these admissions. Cardiovascular effects of cocaine are being extensively studied using various species of animals as model systems. Recent research in rabbits has focused on cocaine's sodium channel blocking (local anesthetic) properties. In anesthetized rabbit's cocaine produces a widening of the QRS along with decreases in blood pressure and heart rate and in increase in respiration rate. Several class 1 antiarrhythmics have been tested in the same preparation and compared to cocaine. The class 1B antiarrhythmic lidocaine produced similar cardiovascular effects, although cocaine was clearly more potent than lidocaine. However unlike cocaine, lidocaine is not thought to be proarrhythmic. The class 1C antiarrhythmic flecainide and the class 1A drug procainamide produced even smaller effects on QRS and respiration and no effect on blood pressure and heart rate. The Class 1C antiarrhythmic flecainide can be proarrhythmic. The class 1A antiarrhythmic quinidine had effects intermediate to lidocaine and flecainide. These results indicate that while cocaine has effects similar to the sodium channel blocking class I antiarrhythmics, alternative mechanisms of action are involved in cocaine's overall cardiovascular effects, even its proarrhythmic effects. We have previously proposed that cocaine has a novel pharmacodynamic action in rats, characterized by a large, but brief increase in blood pressure and a brief and intense behavioral arousal. Recent studies have indicated that several drugs structurally related to cocaine (CPT, CFT, beta-CIT, norcocaine, cocaethylene and benztropine) have similar effects. The relative potency of these drugs is not correlated with their potencies to bind to dopamine, norepinephrine or serotonin transporters. Several monoamine uptake inhibitors that are not structurally related to cocaine (indatraline, nomifensine, BTCP, mazindol and GBR 12935) failed to produce an effect similar to cocaine. Similarly, several sodium channel blockers (quinidine, acetylprocainamide, prilocaine, dyclonine, proparacaine, dibucaine and tetracaine) failed to produce this effect. These results further support the hypothesis that the rapid pressor response to cocaine may be due to some novel action of cocaine.